NO157566B - PROCEDURE FOR Separation of fatty acid esters from a feed mixture comprising fatty acid esters and colophony acid esters. - Google Patents

Abstract

An ester of a fatty acid is separated from a mixture comprising an ester of a fatty acid and an ester of a rosin acid by contacting the mixture at adsorption conditions with an adsorbent comprising silicalite, thereby selectively adsorbing the ester of a fatty acid. The fatty acid ester can be recovered from the adsorbent by desorption with a desorbent material comprising a paraffinic hydrocarbon. A simulated moving bed counter-current flow adsorption systemn can be used.

Description

Method of manufacture of

19-nor-5(10)-dehydrosteroids with

hydroxyl groups in the 3B and 6S positions.

This invention relates to a new process for the production of new steroid compounds with estrogenic activity.

To date, steroids useful in human therapy and having estrogenic activity have been found to have a fully aromatic ring A. When administered, they are usually found to produce undesirable side effects such as nausea, epigastric pain and, in some cases, vomiting.

It has now been found that certain steroids as defined below with only one or two double bonds in ring A are active as pro-oestrogens, i.e. that they are converted into estrogens after administration to humans, as evidenced by increased excretion in the urine of the estrogen-metabolism products, estrone, estradiol and estriol, reduction of the serum phosphorus value, etc.. Furthermore, it has been found that the administration of these pro-estrogens usually does not cause nausea, and this represents a significant advantage of oral therapy.

The new pro-estrogenic steroids that are manufactured according to

to the invention, are 19-nor-5(10)-dehydrosteroids with hydroxyl groups in the 3B and 6S positions.

With the term "steroids" as used here, shall

is understood to mean compounds which have the cyclopentaneperhydrophenanthrene basic ring structure, and which may contain different substituents, e.g.

an alkyl group such as a methyl group, in a- or B-configuration in the 2-, 6- or 16-position, various substituents in a- or 6-configuration in the 17-position, e.g. a halogen atom, a keto group, a hydroxy group, a hydrocarbon group such as a methylene, ethynyl, haloethynyl, buta-1,3-diynyl or 1,5-dimethylhexyl group, an acyl group such as an acetyl group , an α-hydroxyethyl-

group or a hydroxyacetyl group or a ketal derivative thereof,

a halogen atom such as a fluorine or chlorine atom in the 11- or 12-position, or an iodine atom or an alkyl group in the 18-position.

The new compounds are, as indicated above, active as pro-estrogens and are therefore useful in the treatment of post-

menopausal syndrome, primary amenorrhea, dysmenorrhea, galactorrhea, osteoporosis and acromegaly. They possess the advantage over previously used estrogens that they produce little or no nausea, epigastric pain or vomiting upon administration.

When the steroids contain alkyl groups as substituents,

these preferably have 1-8 carbon atoms. Acyl groups are preferentially

show lower aliphatic acyl groups with 1-6 carbon atoms, such as acetyl groups, or they are aroyl groups such as benzoyl.

A compound that is particularly useful because of its activity as a pro-estrogen and as an intermediate in the development of

the position of other compounds according to the invention is 3B,66-dihydroxy-19-nor-androst-5(10)-en-17-one. The new compounds can also be used as intermediates for the production of other 19-nor-5(10)-dehydrosteroids, e.g. by acylation, dehydration, oxidation or reduction of the 38- and 6B-hydroxy groups.

The new compounds can be suitably used in the treatment of menopausal and postmenopausal syndromes, functional uterine bleeding, postpartum breast engorgement, female hypogonadism, accidents during pregnancy and senile vaginitis. Like other estrogenic compounds, the preparations also work to reduce the serum cholesterol value, and are thus useful for the treatment of hypercholesterolaemia which is associated with high blood pressure, arteriosclerosis and arteriosclerotic heart disease. Either alone or together with progestational compounds, the preparations can also be used as antifertility agents. A further advantage of the preparations is their reduced tendency to cause salt and water retention compared to normal oestrogens. This is of particular benefit in elderly people who have disorders associated with edema.

The new 19-nor-5(10)-dehydrosteroids with hydroxy groups in the 3B and 6B positions can be advantageously prepared by reacting a compound with the partial structure

(where R is a hydrogen atom or an acyl group and Hal is a halogen atom) with alkali, whereby the carbon atom in the 19-position is eliminated and a 5(10) double bond is introduced.

The reaction with alkali is conveniently carried out below

moderately vigorous conditions, i.e. use of an alkali metal hydroxide such as NaOH or KOH at elevated temperature, e.g.

at a temperature between 40°C and the boiling point of the reaction medium. The reaction medium is preferably aqueous, but suitably contains a water-miscible solvent1 for the reagents, e.g.

an alkanol such as methanol or ethanol.

The aldehyde with partial structure v can be prepared by reacting a hemi-acetal or ester thereof with partial structure VI, with alkali under mild reaction conditions for such a long time that the aldehyde is the main product. The alkaline compound can e.g. be alkali metal hydroxide, carbonate etc. in aqueous or aqueous-alkanolic solution, e.g. o.2 N alkali metal hydroxide in methanol-water 5:1 at room temperature for 10 minutes.

The hemiacetal esters with partial structure VI (R = acyl) can e.g. is produced by reacting a dioxide with the partial structure

with a source for positive acyl ions, e.g. an acid, such as an alkanoic acid such as acetic acid, in a strong acid such as a mineral acid such as perchloric acid. If the reaction mixture contains an anhydride, e.g. the anhydride of the alkanoic acid used, one can get increased yields of the di-acyl derivative where R is acyl and an acyloxy group is in the 3-position. The dioxide with partial structure VII can e.g. is produced by reacting an oxime with the partial structure (where R has the above meaning) with an acid, e.g. a strong mineral acid such as hydrochloric acid, suitably in solution in an aqueous polar solvent such as aqueous dioxane. The oxime with partial structure VIII can e.g. is produced by photolysis of a compound with the partial structure

(where R has the above meaning) as described in Belgian patent no. 625669.

It is also possible to prepare the hemiacetal with partial structure VI by reacting the oxime with partial structure VIII with nitrous acid, and this is generally the most appropriate method. Nitric acid can e.g. is formed on site by reaction between a nitrite, e.g. an alkali metal nitrite, and an acid,

e.g. a mineral acid such as hydrochloric or sulfuric acid or an alkanoic acid such as acetic acid.

The invention shall be described in more detail using the following examples where parts and percentages are by weight, and the temperatures are in °C.

EXAMPLE 1

19- norcholest- 5( 10)- en- 3B, 6B- diol

A solution of 5B,66-epoxy-3B-hydroxy-19-oxo-cholestane (150 mg) in 5% methanolic potassium hydroxide (10 mL) and 20% aqueous potassium hydroxide (2 mL) was refluxed on a steam bath for 2 1 /2 hours. After cooling, the reaction mixture was diluted with water and extracted with methylene chloride. Workup in the usual way and crystallization from acetone gave needles, m.p.

165 - 168° (100 mg), [α]^3+ 98° (c, 0.89); V ^5 3300 (very powerful), 3200 (shoulder) c' m" -j .mei .Ks •

EXAMPLE 2

3B, 6B- dihydrohydroxy- 19- norandrost- 5( 10)- en- 17- one 3 B-acetoxy-6 B-hydroxy-5a-bromo-19-oximino-androst-17-one (10 g) dissolved in glacial acetic acid (200 mL) and water (50 mL) were heated to 70°, sodium nitrite (5 g) was added, and the reaction mixture was held at 70° for an additional 4 minutes. The product was cooled to 0°C, quenched with saturated sodium chloride, extracted with methylene chloride and washed successively with saturated sodium bicarbonate solution and water, and dried (Na 2 SO 4 ). Concentration gave a mixture of the hemiacetal and the hemiacetal acetate which was not separated but used as such.

The crude mixture was dissolved in methanol (50 mL) and a solution of potassium hydroxide (5 g) in water (20 mL) and heated on a steam bath for 3 hours under nitrogen. The reaction mixture was concentrated, diluted with brine, extracted with methylene chloride, and the extracts were washed with water, dried and concentrated. The resulting oil (4.4 g) was chromatographed on magnesium silicate (200 g) to give the diol (3.3 g) recrystallized as needles from ethyl acetate, mp 136-140°. The analytical sample had m.p.

140 - 143°, [a]J<2> + 192° (c, LOO);^<*>^ 3550 (strong), 3400

(strong), 1720 (very strong) cm<-1>.

Found: C: 74.31; H: 9.15; 0: 16.53.

C18<H>26°3 requires: C: 74.44; H: 9.02; 0: 16.53%.

Claims (3)

1. Process for the production of 19-nor-5(10)-dehydro steroids with hydroxyl groups in the 3B and 6B positions, characterized in that a steroid with the following structure in the A and B rings where R is a hydrogen atom or an acyl group, is reacted with alkali, whereby the carbon atom in the 19-position is eliminated and a 5(10) double bond is introduced. 2. Method as stated in claim 1, characterized in that the reaction with alkali is carried out with aqueous, strong alkali under strong conditions, preferably between 40°C and the boiling point of the reaction mixture. 3. Method as stated in one of claims 1 and 2, characterized in that the reaction with alkali is carried out in the presence of a water-miscible solvent for the reacting substances, preferably an alkanol.